The overall theme of this project is the mechanisms by which cytoplasmic kinase cascades are regulated, and how they impinge on their downstream nuclear effectors. Historically speaking, the collaboration between the labs in this project started with work on the Raf-1 kinase in the Sedivy lab. The objective at the time was to find new protein substrates; instead, a novel kinase inhibitor protein, RKIP, was discovered. The shift of focus to the regulation of MAPK signaling forged a natural link with the DeLong lab, who was studying the roles of protein phosphatase 2A (PP2A) by designing novel dominant-defective mutants. Since neither RKIP or PP2A are MAPK pathway specific, the more general theme of how kinase cascades are regulated by dephosphorylation and inhibitory protein-protein interactions became the shared interest. At about the same time a link was established with the Rosmarin lab, whose focus is the Ets family transcription factor GABPalpha, a known target of MAPK signaling. Although the Rosmarin lab is working primarily on downstream signaling by GABPalpha, the key role of GABPalpha, in myeloid cell differentiation provided a very different biological twist to MAPK signaling than the simple proliferation-based fibroblast models previously used by the DeLong and Yeung labs, and this interest sparked new interactions between the labs. The last recruit into the circle of common interests was the Chin lab, when (almost simultaneously) Yeung discovered that RKIP also interacts with kinases in the NF-kappaB pathway, and Chin discovered yet another novel kinase inhibitor protein acting in the NF-kappaB pathway. Thus, the thematic interest shared by the four labs was expanded to include the NF-kappaB pathway, and yet another family of protein kinase inhibitors. The your young labs and the one more established lab have established an informal yet close affiliation that is characterized by frequent hallway consultations, sharing of reagents, and advice on protocols. It is hoped that this can develop into even close interactions by virtue of sharing the proposed COBRE project.